Activation of endogenous glucose production (EGP) was examined in non-diabetic (N=12) and type 1 diabetic (DM1, N=8) subjects while lowering plasma glucose (PG) from clamped euglycemia (~100 mg/dl; 5.6 mmol/L) to values just above the threshold for epinephrine (EPI) and glucagon secretion (~70 mg/dl; 3.9 mmol/L). To induce physiologic hyperinsulinemia (HIns), insulin infusions were fixed at 20% above the rate previously established that maintained euglycemia during somatostatin (250 5g/hr), glucagon (1.0 ng.kg-1.min-1), and GH (3.0 ng.kg-1.min-1) infusions without need for glucose infusion. In nondiabetic subjects, PG was reduced from 5.410.1 mmol/L to 3.910.1 mmol/L in the Experimental protocol, and held constant (5.310.2 mmol/L and 5.5mmol/L) in Control protocol. In the latter, with constant Hins (plasma insulin=12616 pmol/L) and euglycemia, EGP (estimated by [3H-3]-glucose) fell to values 40% of basal (p<0.01). In contrast, in the Experimental protocol at comparable HIns but with PG at 3.910.1 mmol/L, EGP was activated to values ~2-fold higher than euglycemic Control (p<0.01), without significant changes in plasma EPI or glucagon. In DM1 subjects, EGP failed to increase in the face of HIns (84118 pmol/L) and PG=3.910.1 mmol/L. The decrease from basal EGP at this level of PG in DM1 subjects (4.411.0 5mol.kg-1.min-1) was nearly 2-fold that in nondiabetics (2.510.8 5mol.kg-1.min-1, p<0.02). When PG was stepped lower to frank hypoglycemia (~3.1 mmol/L), the failure of EGP activation in DM1 subjects was even more profound but associated with a 50% reduction in the plasma EPI response (p<0.02 compared to nondiabetics). Thus, glucagon- or EPI-independent activation of EGP may be an early step in glucose counter-regulation in humans, and is impaired or absent in DM1.